JPH01287076A - 10-dihydro-10-deoxo-aza erythronolide a compound, production thereof, production intermediate and anti-inflammatory composition - Google Patents

Abstract

NEW MATERIAL: A 10-dihydro10-deoxo-11azaerythronolide A compound of formula I (wherein R₁' is a lower alkyl or a lower alkanoyl; and R₂, R₃ and R₄, which may be the same or different from each other, are each H or a lower alkanoyl) and an acid adduct thereof.

EXAMPLE: 6-O-desosaminyl10-dihydro10-deoxo11-ethyl-11azaerythromycin A.

USE: Useful as an anti-inflammatory, effective for the treatment of inflammatory diseases of humans and animals.

PREPARATION: For example, 10-dihydro10-deoxo-11-alkyl11-azaerythromycin A of formula II (wherein R₂' is desosaminyl; R₃' is cladinosyl; and R₄' is H) is hydrolyzed in one or two steps, or a compound of formula III is reacted with an aliphatic aldehyde of formula IV (wherein R⁵ is H or a lower alkyl), and the product is optionally acylated with a lower aliphatic acid anhydride to obtain a compound of formula I.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides novel biologically active 10-dihydro-10
- Deoxo-11-azaerythronolide A compounds and their pharmaceutically acceptable acid addition salts, their production methods, their production intermediates, and pharmaceutical compositions, particularly anti-inflammatory compositions, containing them as active ingredients. .

(Prior art and problems to be solved by the invention) In addition to their basic antibiotic bactericidal activity, many antibiotics have
It is known that some substances also exhibit anti-inflammatory effects. However, in order to prevent microorganisms from acquiring resistance to these antibiotics too quickly,1 and to avoid the possibility of human tissues becoming hypersensitive to these antibiotics, The inflammatory effect is characterized by inflammation that is not induced by pathogenic microorganisms.
ryprocess) is rarely used for treatment. Therefore, there was a need for antibiotics that have anti-inflammatory activity but at the same time do not have antibiotic bactericidal activity. These substances are compounds whose chemical structures do not resemble those of antibiotics, such as snails, but in exceptional cases they can be obtained from antibiotics by chemical conversion. That is, such an example is C Abr, which is known as D-henicillamine derived from penicillin.
[Nature J 151.107 (I
943) and Ru1z-Torres [Arzne
imittel-ForStl, J 24. '7
14 (I974)].

10-dihydro-1O-deoxo-11 is produced by a technique known in the prior art with recognized practical value, in which erythromycin A oxime is subjected to Beckmann rearrangement and the resulting erythromycin A iminoether is reduced. -Aza-erythromycin A was synthesized (
U.S. Patent No. 4,328,334 (I982
Tsukirise and Djoki6 et al., “J. Chem.
Soc, Perkin Trans, Jr, t
9g6.1881 reference R). The resulting amine, i.e., 10-dihydro-10-deoxo-11-aza-erythromycin A, is reductively methylated with formaldehyde in the presence of formic acid according to a partial modification of Eschwaller Φ-Clarke method by N-methyl -11-Aza-
10-deoxo-10-9 hydroerythromycin A was synthesized as described in British Patent No. 2,094,293 (
Kobrehel and Djokic! )reference〕. This is a novel semi-synthetic macrolide antibiotic of 15-membered ring azalactone.
It is being used in clinical trials under the common name cin.

U.S. Patent No. 4,464,527 (I984/8
10-dihydro-10-7'oxo-11
- N-ethyl derivative of azaerythromycin A and N
-(n-zolopyl) derivatives are described.

These derivatives are also effective antibacterial agents.

(Means for Solving the Problems 1 Actions and Effects) According to a prior art investigation conducted by the present inventors, 10-dihydro-10-deoxo-11-azaerytholide (a
It has become clear that compounds such as zaerythronolide) A, in particular their N-alkyl derivatives, their salts and/or 0- and/or N,O-substituted alkanoyl derivatives, have not been described in the literature.

That is, according to the present invention, the following formula (I) (wherein R1 represents a hydrogen atom, a lower alkyl group, or a lower purchamyl group, R2, R3 and R4 have the same or different meanings, and each represents a hydrogen atom) or lower alkanoyl group) 10-dihydro-10-deoxo-11
-7 The process for producing a compound of the chemical lithronolide A and, if desired, a pharmaceutically acceptable acid addition salt thereof, which method comprises the following formula (II) (wherein R1 is 10-dihydro-10-deoxo-11-alkyl-11-azaerythromycin, which has the following meaning, uS! represents a desothy≠saminyl group, 1 represents a cladinosyl group, and R2 represents a hydrogen atom) A is hydrolyzed in one or two steps, or as method (B), 10-dihydro-10-deoxo-11 of the following formula (Ill) in the presence of formic acid or with a noble metal catalyst in the presence of hydrogen -Azaerythronolide A with the formula % (in the formula, R5 represents a hydrogen atom or a lower alkyl group)
and (C) method, if desired, the above-mentioned method (A) or (
B) Acylation of the product obtained according to the process with a lower aliphatic acid anhydride and, if desired, the above-mentioned (A), (B) or (C).
Converting the product obtained according to the method into a pharmaceutically acceptable acid addition salt provides a process for the preparation of a compound of formula (I) or an acid addition salt thereof, characterized in that it consists of:

Hydrolysis according to the method (A) of the production method of the present invention is carried out in one or two stages. In carrying out the one-step hydrolysis method, the hydrolysis is carried out using a highly concentrated inorganic acid in the presence of an inert solvent, e.g. chloroform, heated under a reflux condenser for 16-60 hours, then heated to -8 9 by extraction and isolation of the product with the same solvent (chloroform).

In a two-step hydrolysis method, mycin A is hydrolyzed with a dilute inorganic acid at room temperature for 10-20 hours, resulting in an intermediate of formula (v) (wherein R1 and R'2 are defined above). bo-desosaminyl-Io->hydro-IQ-
extracting the deoxo-11-alkyl-11-azaerythromycin A at pI''!9-11 into a non-solvent, such as methylene chloride, chloroform or diethyl ether; and (I1) then the isolated intermediate ( V) is subjected to hydrolysis as described in the one-step process above.

Method (B) of the production method of the present invention consists of reductive alkylation of the compound 10-dihydro-10-deoxo-11-azaerythronolide A of the formula (Ill), and method (B1) comprises using formaldehyde, an example of an aldehyde of formula (IV), in the presence of formic acid; or, as method (B2), using an aldehyde of formula (rV) as described above in the presence of hydrogen and a noble metal catalyst in an inert solvent; It is done either by or.

Among the methods of the present invention, according to method (B), the above compound (+10) is mixed with formaldehyde in an excess of 1 to 3 molar equivalents and at least the same amount of formaldehyde in an inert solvent, such as acetone, halogenated hydrocarbon, preferably chloroform. The reaction mixture was reacted for 2 to 8 hours at the reflux temperature in the presence of an amount of formic acid, and the reaction mixture was reacted for 2 to 8 hours at the reflux temperature of the reaction mixture.
and a compound in which R4 represents a hydrogen atom, namely 10-dihydro-10=deoxo-11-methyl-11-7zaerythronolide A, is obtained.

(B2) Process comprises preparing the compound (I) in the presence of hydrogen and a noble metal catalyst in an inert solvent, e.g.
1) It consists of reductive alkylation of I O-dihydro-10-deoxo-11-azaerythnolide A with the aldehyde of formula (IV) above. In practice, this reaction is carried out using a 1-2 times molar excess of aldehyde and 0.5 to equimolar amount of noble metal catalyst, preferably Pd/C (palladium on carbon) (5% wt/MW). . Reductive alkylation at 10-30 bar at the beginning of the reaction
In a hydrogen atmosphere with a hydrogen pressure of
It is carried out for 2-10 hours at 25°C. After completion of the reaction, the catalyst is filtered, the product is isolated by conventional methods, the alcohol is evaporated, most suitably under reduced pressure, and the aqueous suspension obtained is dissolved in an inert organic solvent such as methylene chloride, chloroform, etc. Or by extraction with carbon tetrachloride, R1 in the obtained formula (I) represents a lower alkyl group, and R
10-dihydro-10-deoxo-11, the product of formula (I) above, wherein 2, R and R4 each represent a hydrogen atom;
-Alkyl-11-azaerythnolide A is obtained and isolated.

According to method (C) of the production method of the present invention, that is, the above (
In the case of the above-mentioned acylation of the products obtained according to method A) or method (B), the acylation is carried out according to standard acylation methods [for example, Jones et al. [J, Med.

Chem,, J 15.631 (I'?72)
] can be done.

Furthermore, according to the second invention, the following formula (IA)R'
l (wherein R1 has the same meaning as R1 except that it is not a hydrogen atom, and R2, R5 and R4 have the meanings defined above), Ride A compounds and their pharmacology! Acid addition salts are provided.

The above formula when R1 in formula (I) represents a hydrogen atom (
I) Io-:) Hydro-10-deoxo-11-azaerythronolide A compound itself prior art VCB
4 (see S. Djokid et al., J. Chem.
.

Soc, Perkin Trans I J I'
? g6.1881). However, we have now invented a new and improved process for the preparation of compounds of formula (I) by method (A)K as defined above and also of formula (I).
) discovered a new pharmaceutical use for the compound. lo
-:) Hydro-IQ-deoxo-11-azaerythronolide A The pharmaceutically acceptable acid addition salts of Compound (I), which are also encompassed by the present invention, are I□->hydro-10
-thioquino-11-azaerythronolide A compound (I
) with a small amount (and equimolar amounts of a suitable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, citric acid, cono-phosphoric acid, benzoic acid, etc.) and an inert solvent if desired. The acid addition salts can be obtained by reaction under the reaction conditions described above in the presence of the acid addition salts, if they are not soluble in the inert solvent used, by filtration, or by precipitation, which is carried out by adding a non-solvent of the corresponding salt. or by evaporation of the solvent, most often by lyophilization.

Furthermore, according to the invention, 10-
Pharmaceutical compositions containing active compounds of dihydro-10-dioquine-11-azaerythronoid A compounds or their pharmaceutically acceptable acid addition salts are provided, which are useful for the treatment of inflammatory diseases in humans and animals. The present invention is utilized in methods for producing pharmaceuticals containing the compound of formula (I) as described above.

in vitro and in vivo
+0- of the above formula (I) by in vivo) tests:
) We have found that hydro-10-deoxo-11-azaerythronoid A compound exhibits strong anti-inflammatory activity. The anti-inflammatory effect of the compound of the formula (RI) was demonstrated by a model test method for the extracellular release of lysosomal enzymes by human polymorphonuclear leukocytes [Weissman et al., J. Exp. Med.
,, J134, 149 (I971); Carev
It! , Agents and Acting, 1
6.407 (I985)) in vitro (i
diclofenac (hereinafter referred to as DICL), which is a known anti-inflammatory agent, and D+<
The anti-inflammatory effect was compared with that of nidiramine (hereinafter referred to as D-PEN). The results obtained are shown in the attached graphs of FIGS. 1 and 2.

From Figure 1, the hydrolysis product of azithromycin 10-
Dihydro-10-deoxo-11-methyl-11-azaerythronolide A (hereinafter referred to as AZER) and the corresponding 6-0-desosaminyl derivative product 6-0-desosaminyl-10->hydro-10-deoxo-11 It is clear that -methyl-11-7 zaerythromycin A (hereinafter referred to as DESAZ) has a good anti-inflammatory effect.

At a concentration of 10-5 molar, DESAZ exhibits approximately the same activity as D-PEN at a concentration of 10 molar. IQ-:)hydro-10-deoxo-11- by elimination of two sugar groups
Methyl-11-azaerythronolide A (hereinafter referred to as AZER)
The synthesis of D-PgN, which strongly inhibits the extracellular release of lysosomal enzymes from human polymorphonuclear leukocytes, is obtained, similar to D-PgN, a compound with strong activity at a concentration of 10 molar. It has the activity of

In vitro, DICL does not affect the extracellular release of the enzyme. N-ethyl-derivative 10-dihydro-1
0-deoxo-11-ethyl-II-azaerythronolide A (hereinafter referred to as AE) or N-(n-propyl) derivative 10-dihydro-10-deoxo-II-(n
-propyl)-11-azaerythronolide A (hereinafter A
PR) has somewhat lower activity than AZER (see Figure 2). Furthermore, an acylated product of AZER with acetic anhydride, namely 4,6.13-triacetyl-1o-:
) Hydro-10-deoxo-11-methyl-11-azaerythronolide A (hereinafter referred to as ALA-3) shows no substantial change in anti-inflammatory activity in in vitro tests.

Arthritis model induced in rats with adjuvant (P
“Arthritis Rheum,” by erason et al.
, J2.

440 (I959); Carevid's Publ
, Yug, Acad, ofSct,, 7,41
5 (I985)] in vivo.
) tests were also conducted. From Figure 3 showing the results, it was confirmed that AZER significantly reduced the extracellular release of lysosomal enzymes into the synovial fluid of rats with adjuvant arthritis and that AZER significantly reduced the activity of D-PEN. It can be seen that it shows a level of activity comparable to that of DICL and is considerably higher than that of DICL.

It showed somewhat lower activity than DESAZ tiD-PEN and DICI.

It is clear from the above test results that the in vivo test method can be compared and contrasted with the analytical results of the in vitro test method. In these tests, the compounds tested in vitro and in vivo have no significant effect on the release of the enzyme lactate dehydrogenase (hereinafter referred to as A). This indicates that cell membranes are not significantly affected.

The anti-inflammatory activity of the compounds of the present invention was also demonstrated in rat paw M (p
aw) as measured by the evaluation of the inhibitory effect on carrageenan-induced edema (Crunkhorn et al., Br, J.

Pharm, J 42.392 (I971)).

The results obtained with the compound (I) of the invention (see Table 1) demonstrate that D-PEN and acetylsalicylic acid (Ac15
al (registered trademark)].

N-ethyl derivative 10-dihydro-10-deoxo-11-ethyl-11-azaerythronolide A of the present invention
(AE) and N-(n-propyl) derivative 10-dihydro-10-deoxo-II-(n-propyl)-1
1-Azaerythronolide A (APR) has a similar level of anti-inflammatory activity as AZER. 〇- of formula (I) of the present invention
Substituted conductors and N,0-substituted derivatives, e.g. 4.6.1
3-Triacetyl-10-dihydro-10-thioquine-
11-Methyl-11-azaerythronolide A (AL
A-3) or +0-:) Hydroherthoquine-11-methyl-11-azaerythronolide A hydrochloride (hereinafter referred to as AZ
ER・HC7) has improved anti-inflammatory activity compared to D-PEN K, but exhibits almost the same anti-inflammatory activity as acetylsalicylic acid.

K K 2
ni=to;ki -
;3+ +
a O-6 − U< − 1 −−to 2 − 1 −−I Ma −oI
1 ＼ ＼ −
Sa \ir e
Ki 1 Ro
Ir+＜4+H+'' 2 M - Tan Be - S Tan 2 included
Ma -＼ Ma sa p -Iso to Ma II
to tX11 r )l −, o
Also hot ihe Q \ lobe o)
, S 0 ＼-ro-ro
− To taste
-nn ″″ (Examples) The present invention will be explained by the following examples, but these are not intended to limit the invention in any way.

Example 1 Preparation of azaerythronolide A 10-dihydro-10-deoxo-11-azaerythromycin A (I00F, 136.06 mmol), 6M-HCl (750 ml) and CHC/,
The mixture of (380-) was kept boiling under a reflux condenser for 16 hours. After cooling to room temperature, the resulting aqueous phase was extracted with chloroform (2 x 100 m). -1 of the aqueous solution was adjusted to 5.0 by addition of aqueous sodium hydroxide solution, then chloroform (3x10
0+a/). The same operation was repeated with p118.5 (3x250-). The chloroform extract of -8,5 was dried over 2C03 and then evaporated under reduced pressure to yield 53.77 t of crude 10-dihydro-10-deokine-11-azaerythronolide A (yield, 74.2%).
) was obtained. This was recrystallized from diethyl ether (300m) [J, Chem, Soc.

Perkin Trans, t J 1986.1S
A homogeneous product with physicochemical constants as described in L (thin layer chromatography, developing solvent: c6H
6:cHcz3:crt, oH: 40:55:l,
NH,,R (value: 0.233) was obtained at 34.45F.

Example 2 Monomethyl-11-azaerythronolide azithromycin (N-methyl-11-aza-10--F'oxo-t
O-:) Hydroerythromycin A1 formula (II))
(IO?, 13.35 mmol), 6M-HC/
(75sg) and chloroform (3g, d) was kept boiling under a reflux condenser for 48 hours. After the resulting reaction mixture was cooled to room temperature, the layers were separated, and the resulting aqueous layer was extracted with chloroform. The aqueous layer was adjusted to -5.0 with an aqueous sodium hydroxide solution, extracted again with chloroform, and the same operation was repeated with 1 g of Kujime and 5. A chloroform extract was obtained at pl[, 5 and about 1 of
It was concentrated to a volume of t/m and left to crystallize. After filtering the precipitated crystals and drying them, the product 10-dihydro-10-deoxo-11-methyl-11
-7 Zaerythronolide A 4.7 f (yield 81.
2%). It can be recrystallized from chloroform if desired. Melting point 208 to 210°C0 Elemental analysis CHNC22II
43NO and shell: Actual value (I) 60.9. it I
O,,OO3,23 theoretical value (4) 60.72'?
, 632. '? 6 Example 3 Erythromycin (N-methyl-11-aza-10-deoxo-1o-:)hydroerythromycin A) dissolved in 0.25M HC/(500m/) (I0t,
13.35 mmol) was allowed to stand at room temperature for 15 hours. Add this to chloroform (3X75wd
), and the extract was washed with IM-HC/and water. The resulting aqueous layers were combined, made pl (IOK) alkaline with an aqueous sodium hydroxide solution, and then extracted again with chloroform.
Dry with CO3 and then evaporate the chloroform to dryness under reduced pressure.

The obtained crude product was washed with ether and the product i.e. 6-0-desosaminyl-10-dihydro-IO-deoxo-11-methyl-11-azaerythromycin A 6
．． 9 t (yield: 7.8%) was obtained.

Melting point 2035205°C0 Elemental analysis value CHNC3
As 0H5BN209: Actual measurement value C @ 60.9'
? '? , 90 2.96 Theoretical value (to) 60.63
9.58 4.36 Example 4 Following the method described in Example 1, the product obtained in Example 3 namely 6-0-desosaminyl-10-dihydro-1
The product obtained in Example 2 from 0-deoxo-11-methyl-11-azaerythromycin AlO2, namely 10-
Dihydro-10-deoxo-11-methyl-11-azaerythronolide A6.56f (yield: 89.4%) was obtained.

Example 5 Preparation of A 10-dihydro-10-deoxo-11-azaerythronolide A (20I!1/) dissolved in chloroform (20I!1/)
IF, 2.38 mmol) in formaldehyde (
Concentration 36) 0.1 4 td (2,38 mmol) and formic acid C 8 degrees 98-1004' I O, 1 g 4 m (4,7 mmol)
7 mlJ mol) was added and the reaction mixture was refluxed for 8 hours under stirring. The resulting reaction mixture was then cooled to room temperature, left undisturbed for 24 hours, and the precipitated crystals
washed with chloroform, then dried to give a crude 10-
:) Hydro-10-deoxo-11-methyl-11-azaerythronolide A1. CM' (yield 96.5%) was obtained. It can be recrystallized from chloroform if desired (R value of 0.306'' in thin layer crystallography).

Melting point 208-210°C0'HNMR (CD, 00n δ: 2.351
pr) m (N-CI(5) Example 6 Preparation of A Ethanol (concentration 96%') (50 m) Ic dissolved 1
A solution of 0-dihydro-10-deoxo-11-azaerythronolide A (59.
2.5f) was added, and then the reaction mixture was diluted with 2.5f) under stirring.
Hydrogenation was carried out for 10 hours under a hydrogen pressure of 0 bar. The catalyst was filtered from the resulting reaction mixture, washed with ethanol (20 sd), and the liquid phases were combined and concentrated to a volume of about 30 mL by evaporating the solvent under reduced pressure. Water (100 t/) and chloroform (50 m) were added to the obtained reaction mixture, the ril of the liquid was adjusted to pfl 4.5 K by adding 2 M-MCI, and then the liquid was separated, and the obtained aqueous layer was Nariroroform (2xsomx)
extracted again.

After adjusting the alkaline pH of the solution to pH 8.5 with an aqueous solution of IJ (hydroxide), add chloroform (3X50
-), the combined chloroform extracts were dried over 2CO3, and then the chloroform was evaporated under reduced pressure to produce the crude jO-dihydro-10-7'oary-11-ethyl-11-azaerythronolide A4.68. ? (
A yield of 87.2%) was obtained. The obtained product was suspended in diethyl ether (LOM) and stirred at room temperature for 1 hour,
The precipitate obtained was washed with diethyl ether and then dried to give a product which appeared homogeneous on chromatographic analysis, i.e. 10-dihydro-10-thioquine-11.
-Dithyl II-azaerythronolide A (Rf value in thin layer chromatography: 0.390) 3.29
I got it.

Melting point 204-206°c0 Example 7 Preparation of 0-nolide A 1 dissolved in ethanol (concentration 96%) (60+ag)
A solution of 0-dihydro-10-deoxo-11-azaerythronolide A (6t, 14.30 mmol) in propionaldehyde (I 1.4 m, 157.
31 mmol) and carbon-supported ζ radium (3,0?
Hydrogenated for hours. The reaction mixture obtained was filtered with a catalyst, and the solvent was evaporated under reduced pressure to form a thick liquid.
The product was then isolated by single gradient extraction. Water (I0 (it/)) and dichloromethane (sob) were added to the obtained reaction mixture, and the pH of the liquid was reduced with 2 M-He/.
The fl was adjusted to 4.5, then the layers were separated and the resulting aqueous layer was extracted again with dichloromethane (2X50-). After making the liquid alkaline with an aqueous sodium hydroxide solution, -6,
dichloromethane (IX l 50m, 2X50mj
) The extraction process was repeated. The organic extracts at pHg, s were combined and filtered, the resulting Fi solution was concentrated to a thick suspension by evaporating the dichloromethane under reduced pressure, the separated crystals were filtered and diluted with dichloromethane. The title compound 10-dihydro-10-deoxo-1 is washed and dried and appears homogeneous by chromatographic analysis.
1-,(n-propyl)-11-azaerythronolide A (R in thin layer chromatography (value 0.4+5)
I got it.

Yield i4.39 (yield 65.2%) O melting point 2+2-216
0C Example 8 Preparation of 0Nolide A Pyridine (30d) K dissolved tO-:) Hydro-10
-thioquine-11-methyl-azaerythronolide A (
st, +1.53 mmol) in acetic anhydride (3
0d) was added and the reaction mixture was left to stand at room temperature for 2 hours. The acylation reaction was stopped by adding ice to the reaction mixture and the resulting product was
It was isolated by extraction with chloroform (3×50d). The organic extracts were combined and dried over 2Co, then the chloroform was evaporated to give 3.4f of the crude product.
I got it.

The crude product was suspended in diethyl ether (LOMJ) and the suspension was stirred at room temperature for 1 hour and then filtered to give the title compound 4-0-acetyl-10-dihydro-10-
Deoxo-11-methyl-11-azaerythronolide A (Rt in thin layer chromatography @ o, 56a
) 1.75y (yield 53.2%) was obtained. Melting point 1
87-189 °C0 IR (KBr): 1725 (C=O lactones and esters) and 1235 cm (OAc) 'HNMR (CD50D) δ: 2.343 (s, 3
H,N-0M3), 2.052(s, 3H,4-O
Ac) and 5.227 p pm (d s + u
*4-H) -A corresponding 4-0-propionyl derivative was produced in the same manner except that acetic anhydride was replaced with propionic anhydride.

Example 9 1-"J" 7 (50ml) K dissolved 1o-
Acetic anhydride (50d) was added to a solution of dihydro-10-deoxo-11-methyl-11-azaerythronolide A (5, 11.53 mmol) and the reaction mixture was left at room temperature for 7 days. The reaction was stopped by adding ice and the resulting reaction product was then isolated by extraction with chloroform as described in Example 8. The organic extracts were combined, dried over 2CO3, evaporated to dryness in chloroform, and then purified on a silica gel column with CH2Cl2:CI(,OH:NH).
Chromatography was performed using an elution solvent mixture of 2OH: 90:9:1.5.

Both parts of the low-flowing material were combined, the solvent was evaporated from this, and the resulting amorphous product was dried to give a 4.6° Ride A (
An Rf value of 0.337) was obtained by thin layer chromatography. Melting point 180-182°C0IR (KBr): 1
740 (c=o, +I+Stell), 17+5
(C:O.

lactone) and 1240 m (OAc)13CNM
R(CDCl2)δ: 43. I(q, N-Cu2
), 173.5 (s.

C=O lactone) and +70.2° 170, + and +bq, + ppm (s.

C=0 acetate).

Example 1〇1 dihydro-10-deoxo-11-azaepiridine (
10-dihydro-10-deoxo-11 in 50,d)
- From azaerythronolide A (5, Of, 11.9 mmol) and acetic anhydride (50d), the crude +
1-N, 4.6-〇-)lyacetyl-10-dihydro-10-thioquine-11-azaerythronolide A was obtained. The acetylation reaction was stopped after 24 hours, the reaction product was isolated by conventional extraction methods using chloroform, and the resulting precipitate was suspended in diethyl ether (50-) and the reaction suspension was The suspension was stirred at room temperature for 1 hour and then purified by adding one portion of the undissolved title compound plus 1-N,4.6-0-triacetyl-IO-dihydro-10-deoxo-11-azaerythronolide A. Yield 4.
Og f (yield bB, 34>.

M, I), 220-223°C R (value 0.4+7 IR(KBr): 1715 (C=O, lactones and esters).

1605 (NAc) and 12403 (OAc).

1HNMR (CD30D) δ: 2.115 (s, 3
H,N-Ac), 2.053(s, 3H,4-OA
c) and 2. O40ppm (s, 3H, 6-OAc)
.

Example 11 Preparation of monomethyl-11-azaerythronolide A hydrochloride 10-dihydro-10-dioquine-11-methyl-11
-Azaerythronolide A (4,34?.

+ O mmol) to 25 dlC of water! Make it cloudy and add 1 under stirring.
The - of the solution was adjusted to 5.8 by dropwise addition of 0.25 N -1 (C/K) in 1 hour. The clear reaction mixture was stirred for an additional hour at room temperature, filtered and then evaporated. was freeze-dried to give 10-:)hydro-10-dioquino-11-methyl-11-azaerythronolide A hydrochloride 4.48 ?
(yield: 95.5%).

'HNMR (CD30D) δ: 3.03 ppm (
S, 3H, N-CH5) Trace analysis value: Actual value (to) CI 7.54 Theoretical value (to) CI 6
．． 97 In a similar manner, 10-dihydro-IO-deoxo-11-alkyl-11-aza Erythronolide A and its N- and/or
Alternatively, the corresponding salts of N,O-substituted derivatives were obtained.

Example 12 Preparation of A (Method B) According to the method of Example 5, 10-dihydro-10-deoxo-11-azaerythronolide A(+?, 2.
38 mmol), formaldehyde (concentration 36%) (
0,184wd, 2.38 mmol) and formic acid (concentration 98-l O04) (0,183ml 1.4.77 mmol) were reacted with a7ton (201Rt) 0.93 t (yield 89.8 %) was obtained.

Example 13 Preparation of ethyl-11-azaerythronolide (Method B) 10-dihydro-salt 0-deoxo-11-ethyl-11-azaerythromycin A (54,6,55 2.45 r
(Yield & ratio: 3.57) was obtained.

Example I4 Preparation of n-propyl)-11-azaerythronolide A (Process B) Following the method described in Example IK, Io-:)hydro-
The title compound 10-dihydro- with the same physical properties as described in Example 7 using 10-deoxo-1f-(n-propyl)-11-azaerythromycin A (54,6,44 mmol) as starting material. 10-deoxo-1t
-(n-propyl)-11-azaerythronolide h2
．． ht (yield 80.7%) was obtained.

Example 15 IO-dihydro-10-deoxo-11-ethyl-11
-Azaerythromycin A (+?, 1.31 mmol) was dissolved in 0.25 MHC/(50d) and left at room temperature for 16 hours. The resulting reaction mixture was then extracted with chloroform (3X I Od) and the organic extracts were combined and washed with 1 M -HC/and water. The resulting aqueous layers were combined and made alkaline with aqueous sodium hydroxide (IO) and then extracted again with chloroform (3x20d). The resulting chloroform extract was dried over 2CO3 and the chloroform was evaporated. After washing the obtained crude product with ether, the title compound 6-0-desosaminyl-10
-dihydro-10-deoxo-11-ethyl-buzaerythromycin A O,7f (yield 88.4%)
It's wo 4.

'HNMR (CDCI,) δ: 2.24 ppm (s
, 6H,N(0M3)2).

In a similar manner, 6-〇-denosaminyl I+)-:)hydro-10-deoxo-11-(n-propyl)-11-
Hydrolysis of azaerythromycin A results in the corresponding N-
A (n-propyl) visiting conductor was obtained.

[Brief explanation of the drawing]

The drawings show the anti-inflammatory activity of the compound of the present invention and various compounds of known anti-inflammatory agents using a model test method for extracellular release of lysosomal enzymes. Figure 3 shows the anti-inflammatory activity in an in vivo test.

Claims (1)

[Claims] 1. The following formula (I A) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I A) (In the formula, R'_1 represents a lower alkyl group or a lower alkanoyl group, and R_2, R_3 and 10-dihydro-10-deoxo-11-azaerythronolide A compound represented by (R_4 has the same or different meanings and each represents a hydrogen atom or a lower alkanoyl group), and a pharmaceutically acceptable acid addition thereof salt. 2. The compound according to claim 1, wherein the lower alkyl group contains 1 to 3 carbon atoms. 3. The compound according to claim 1, wherein the lower alkanoyl group contains 1 to 3 carbon atoms. 4. The following formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R_1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, and R'_2 represents a desosaminyl group) compound. 5. The compound according to claim 4, wherein the lower alkyl group contains 1 to 3 carbon atoms. 6. The compound according to claim 4, wherein the lower alkanoyl group contains 1 to 3 carbon atoms. 7. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, and R_2, R_3, and R_4 have the same or different meanings. and, if desired, a pharmaceutically acceptable acid addition salt thereof, The method (A) includes the following formula (II) ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R_1 has the above meaning, and R'_2 is a desosaminyl group. 10-, R'_3 represents a cladinosyl group, and R'_4 represents a hydrogen atom)
Dihydro-10-deoxo-11-alkyl-11-azaerythromycin A is hydrolyzed in one or two steps or, as method (B), in the presence of formic acid or with a noble metal catalyst in the presence of hydrogen according to the formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) 10-dihydro-10-deoxo-11-azaerythronolide A shown by the formula R_5-CHO (IV) (where R_5 is a hydrogen atom or a lower alkyl group), and as process (C), furthermore, if desired, the product obtained according to process (A) or process (B) above. is acylated with a lower aliphatic acid anhydride, and if desired, the above (A),
Converting the product obtained according to process (B) or (C) into a pharmaceutically acceptable acid addition salt. Law. 8. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, and R_2, R_3, and R_4 have the same or different meanings. containing a pharmaceutically effective amount of 10-dihydro-10-deoxo-11-azaerythronolide A compound or a pharmaceutically acceptable acid addition salt thereof, each of which has the following formula and represents a hydrogen atom or a lower alkanoyl group: An anti-inflammatory agent composition.